|The pharmacokinetics of perampanel have been studied in healthy adult subjects (age range 18 to 79), adults and adolescents with partial-onset seizures, adults with Parkinson's disease, adults with diabetic neuropathy, adults with multiple sclerosis, and subjects with hepatic impairment.|
AbsorptionPerampanel is readily absorbed after oral administration with no evidence of marked first-pass metabolism. Food does not affect the extent of absorption, but slows the rate of absorption. When administered with food, peak plasma concentrations are reduced and delayed by 2 hours compared with dosing in a fasted state.
DistributionData from in vitro studies indicate that perampanel is approximately 95% bound to plasma proteins. In vitro studies show that perampanel is not a substrate or significant inhibitor of organic anion transporting polypeptides (OATP) 1B1 and 1B3, organic anion transporters (OAT) 1, 2, 3, and 4, organic cation transporters (OCT) 1, 2, and 3, and the efflux transporters P-glycoprotein and Breast Cancer Resistance Protein (BCRP).
BiotransformationPerampanel is extensively metabolised via primary oxidation and sequential glucuronidation. Primary oxidative metabolism is mediated by CYP3A based on results of in vitro studies using recombinant human CYPs and human liver microsomes. However, the metabolism has not been completely elucidated and other pathways cannot be excluded.Following administration of radiolabeled perampanel, only trace amounts of perampanel metabolites were observed in plasma.
EliminationFollowing administration of a radiolabeled perampanel dose to 8 healthy elderly subjects, 30% of recovered radioactivity was found in the urine and 70% in the faeces. In urine and faeces, recovered radioactivity was primarily composed of a mixture of oxidative and conjugated metabolites. In a population pharmacokinetic analysis of pooled data from 19 Phase 1 studies, the average t1/2 of perampanel was 105 hours. When dosed in combination with the strong CYP3A inducer carbamazepine, the average t1/2 was 25 hours.
Linearity/non-linearityIn healthy subjects, plasma concentrations of perampanel increased in direct proportion to administered doses over the range of 2 to 12 mg. In a population pharmacokinetic analysis of patients with partial-onset seizures receiving perampanel up to 12 mg/day in placebo-controlled clinical trials, a linear relationship was found between dose and perampanel plasma concentrations.
Hepatic impairmentThe pharmacokinetics of perampanel following a single 1 mg dose were evaluated in 12 subjects with mild and moderate hepatic impairment (Child-Pugh A and B, respectively) compared with 12 healthy, demographically matched subjects. The mean apparent clearance of unbound perampanel in mildly impaired subjects was 188 ml/min vs. 338 ml/min in matched controls, and in moderately impaired subjects was 120 ml/min vs. 392 ml/min in matched controls. The t1/2 was longer in mildly impaired (306 h vs. 125 h) and moderately impaired (295 h vs. 139 h) subjects compared to matched healthy subjects.
Renal impairmentThe pharmacokinetics of perampanel have not been formally evaluated in patients with renal impairment. Perampanel is eliminated almost exclusively by metabolism followed by rapid excretion of metabolites; only trace amounts of perampanel metabolites are observed in plasma. In a population pharmacokinetic analysis of patients with partial-onset seizures having creatinine clearances ranging from 39 to 160 mL/min and receiving perampanel up to 12 mg/day in placebo-controlled clinical trials, perampanel clearance was not influenced by creatinine clearance.
GenderIn a population pharmacokinetic analysis of patients with partial-onset seizures receiving perampanel up to 12 mg/day in placebo-controlled clinical trials, perampanel clearance in females (0.605 l/h) was 17% lower than in males (0.730 l/h).
Elderly (65 years of age and above)In a population pharmacokinetic analysis of patients with partial-onset seizures ranging in age from 12 to 74 years, and receiving perampanel up to 12 mg/day in placebo-controlled clinical trials, no significant effect of age on perampanel clearance was found.
Paediatric populationIn a population pharmacokinetic analysis of the adolescent patients in the Phase 3 clinical studies, there were no notable differences between this population and the overall population.
Drug interaction studies
In vitro assessment of drug interactions
Drug metabolising enzyme inhibitionIn human liver microsomes, perampanel (30 μmol/l) had a weak inhibitory effect on CYP2C8 and UGT1A9 among major hepatic CYPs and UGTs.
Drug metabolising enzyme inductionCompared with positive controls (including phenobarbital, rifampicin), perampanel was found to weakly induce CYP2B6 (30 μmol/l) and CYP3A4/5 (≥3 μmol/l) among major hepatic CYPs and UGTs in cultured human hepatocytes.